Pathogenic role of a protein complex of liver origin as regulator of a proinflammatory program that drives hepatic and intestinal injury in alcoholic liver disease

Jesse Brown Va Medical Center, Chicago IL

Investigators

Linked publications & trials

Abstract

ABSTRACT Inflammation is a hallmark of alcohol-induced liver injury. Numerous studies established the role of the gut-to- liver axis, but there is limited information on how the liver-to-gut axis contributes to inflammation and injury in alcoholic liver disease. It is unknown whether ethanol-induced sterile damage-associated molecular patterns of liver origin activate a proinflammatory program that, besides being detrimental to the liver, drive intestinal barrier dysfunction, hence creating an amplifying proinflammatory feedback loop in alcoholic liver disease. Our overarching goal is to dissect the pathogenic role of a protein complex of liver origin in regulating a proinflammatory program that drives hepatic and intestinal injury in alcoholic liver disease. In prior work, we demonstrated that high-mobility group box-1 (HMGB1) is a damage-associated molecular pattern up-regulated in response to liver injury and participates in the pathogenesis of alcoholic liver disease. Interestingly, HMGB1 undergoes oxidation only in hepatocytes, and serum levels of oxidized HMGB1 ([O]HMGB1) are increased in alcoholic patients. Our preliminary data demonstrate that blocking the production of [O]HMGB1 in hepatocytes or ablating an HMGB1 receptor (the receptor for advanced glycation end- products, RAGE) in myeloid cells prevents inflammation, hepatic injury, intestinal barrier dysfunction and alcoholic liver disease. We show that Kupffer cells and infiltrated macrophages are the main hepatic source of IL1β. Importantly, we reveal that [O]HMGB1 forms a complex with IL1β. This complex binds RAGE in Kupffer cells and macrophages to produce a proinflammatory program and increases gut permeability in alcoholic liver disease. These encouraging data suggest that a proinflammatory feedback loop initiated by this complex, could exacerbate hepatic and intestinal injury in alcoholic liver disease. However, key mechanistic aspects of how this complex promotes the pathogenesis of alcoholic liver disease remain to be elucidated: 1) whether this complex is of liver origin; 2) whether it is a ligand for RAGE; 3) the signals this complex conveys in Kupffer cells and macrophages to induce a proinflammatory program that exacerbates hepatic injury; 4) whether it alters tight junction protein expression in intestinal epithelial cells and increases intestinal barrier dysfunction; and 5) whether the proinflammatory program itself also contributes to intestinal barrier dysfunction. We propose a conceptually novel framework of a liver-to-gut proinflammatory feedback loop in alcoholic liver disease. Our central hypothesis is that this complex is of liver origin and binds RAGE in Kupffer cells and macrophages to induce a proinflammatory program that exacerbates hepatic injury. By binding RAGE in intestinal epithelial cells and/or by inducing the proinflammatory program, this complex alters tight junction protein expression and increases intestinal barrier dysfunction. We will test this hypothesis by pursuing three specific aims. In Aim 1, we will identify the complex as being of liver origin. In Aim 2, we will determine the complex binding affinity for RAGE in Kupffer cells and macrophages and identify the signals through which the complex induces a proinflammatory program that exacerbates hepatic injury. In Aim 3, we will determine if the complex alters tight junction protein expression and increases intestinal barrier dysfunction by binding RAGE in intestinal epithelial cells and/or by inducing the proinflammatory program. Therefore, targeting this complex could have significant therapeutic potential.